The objective of the proposed research is to validate the efficacy of urinary porphyrin profile measurements as a biomarker of mercury (Hg) exposure, Hg-induced neurobehavioral effects and Hg body burden in human subjects. The long-term goal is to provide a sensitive and accurate biomarker of Hg exposure and effects which can be used to reduce the incidence and severity of Hg toxicity in people with low-level environmental exposure. The specific aims of the project are to (1) describe individual human variability in urinary porphyrin and Hg excretion rates in spot urine samples, and determine the extent to which spot urine samples are representative of 24 hour porphyrin and Hg excretion rates, (2) determine the sensitivity of urinary porphyrins as a measure of sub-chronic and chronic low-level Hg exposure, (3) determine the sensitivity of urinary porphyrins as a measure of neurological effects associated with low-level Hg exposure, and (4) determine the sensitivity of urinary porphyrins as a measure of Hg body burden. These objectives will be accomplished by evaluating urinary porphyrin profiles with respect to their correlation with specific measures of Hg exposure, neurobehavioral function and cumulative Hg dose among subjects (dentists and dental assistants) with well-characterized, prolonged, low-level Hg exposure comparable to that experienced by persons residing near Superfund hazardous waste sites. Additional specific aims, to be accomplished using an established animal model, are to (5) define urinary porphyrin concentrations as a quantitative measure of mobilizable Hg in the kidney and (6) define the chemical structure and biochemical etiology of an atypical porphyrin, "precoproporphyrin", excreted by mercury-exposed animals and humans. The anticipated outcome of these studies is a well characterized biomarker based on a biological response to Hg in target tissues, which will significantly enhance the assessment of low-level Hg exposure and potential toxicity in human subjects. These studies will also further define the biochemical mechanisms which underlie the specificity of the porphyrinogenic response to Hg exposure.